Characterizing the humoral response to lipoarabinomannan in tuberculosis progression

描述结核病进展中对阿拉伯脂甘露聚糖的体液反应

• 批准号: 10548577
• 负责人: Leela Davies
• 金额: $ 19.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548577
• 关键词: Adolescent; Animal Model; Antibiotics; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Bar Codes; Binding; Bioinformatics; Biological Assay; Biological Markers; Biophysics; Cause of Death; Cell physiology; Clinical; Communicable Diseases; Complex; Data; Development; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dissection; Engineering; Ensure; Epitopes; Fc Receptor; Fortune; Foundations; Future; Glycobiology; Glycolipids; HIV; HIV Seronegativity; HIV Seropositivity; Hospitals; IgG1; Immune; Immunoglobulin G; Immunoglobulin M; Immunology; In Vitro; Individual; Infection Control; Institutes; International; Laboratories; Libraries; Mediating; Mediator of activation protein; Medicine; Mentors; Methodology; Microbiology; Monoclonal Antibodies; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; NK Cell Activation; Names; Oligosaccharides; Persons; Physicians; Polysaccharides; Population; Predictive Value; Prevalence; Property; Public Health Schools; Regimen; Research; Resolution; Risk; Role; Serology; South African; Specificity; Surface; System; T-Lymphocyte; Therapeutic; Time; Training; Tuberculosis; Vaccines; Vision; Whole Blood; Woman; Work; antimicrobial; clinically relevant; co-infection; cohort; design; high risk; in vivo; innovation; instructor; interdisciplinary approach; lipoarabinomannan; medical schools; mortality; mycobacterial; novel diagnostics; novel marker; novel strategies; novel therapeutic intervention; predicting response; predictive signature; prevent; receptor binding; response; responsible research conduct; sugar; translational research program

PROJECT SUMMARY/ABSTRACT Reducing progression to active TB disease in individuals infected with Mycobacterium tuberculosis (Mtb) is a key component of eradicating TB worldwide, yet it is hampered by poor predictive value of existing diagnostics, cumbersome antibiotic regimens, lack of understanding of immune mechanisms of control, and absence of an effective vaccine. A growing field of research implicates antigen-specific antibodies as critical biomarkers and mediators of control of Mtb infection, implicating antibodies as the potential basis of novel diagnostic or therapeutic strategies for TB. This proposal describes a five-year research plan to comprehensively investigate the roles of antibodies targeting the mycobacterial glycolipid lipoarabinomannan (LAM) in TB progression in the setting of HIV coinfection. Preliminary data presented indicate that LAM-specific antibodies can predict TB progression in HIV- negative individuals, that they can confer protection against Mtb infection in vitro, and that their recognition of Mtb varies across clinical strains. The LAM epitopes most relevant to immune correlates of TB progression and control of infection, their prevalence across Mtb clinical isolates, and the functional mechanisms of LAM antibody- mediated remain unclear. The studies proposed here aim to 1) define the humoral signatures that predict TB progression in the setting of HIV coinfection, 2) define the breadth and specificity of LAM antibody responses against global Mtb isolates, and 3) define LAM antibody-mediated effector functions that confer antimicrobial control against global Mtb strains. These aims will be approached using an international cohort of HIV-coinfected TB progressors, and make use of innovative methodologies including a powerful systems immunology platform, a panel of synthetic oligosaccharides, a barcoded library of clinical Mtb isolates, and validated in vitro antimicrobial functional assays. The candidate is currently an Instructor in Medicine at Harvard Medical School and an Associate Physician in the Division of Infectious Diseases at Brigham and Women’s Hospital, with an ongoing research commitment of 80% time. The proposal is supported by an expert mentor in humoral immunology, Dr. Galit Alter at the Ragon Institute of MGH, MIT, and Harvard, and an expert co-mentor in mycobacterial diversity, Dr. Sarah Fortune at the Harvard School of Public Health. The training plan unites the candidate’s prior graduate work in glycobiology with specific training in humoral immunology, microbiology, and bioinformatics, as well as ongoing professional development and responsible conduct of research coursework. Completion of this comprehensive training plan will ensure the candidate’s successful development of a unique independent translational research program focused on humoral responses to Mtb glycans.

项目总结/摘要 减少感染结核分枝杆菌（Mtb）的个体进展为活动性结核病 是全球根除结核病的一个关键组成部分，但由于现有结核病的预测价值不高， 诊断，繁琐的抗生素方案，缺乏对免疫控制机制的了解， 缺乏有效的疫苗。越来越多的研究领域涉及抗原特异性抗体作为关键 控制Mtb感染的生物标志物和介质，涉及抗体作为新的抗结核药物的潜在基础。 结核病的诊断或治疗策略。 该提案描述了一项为期五年的研究计划，以全面调查抗体的作用 靶向结核病进展中的结核分枝杆菌糖脂脂阿拉伯甘露聚糖（LAM） 合并感染初步数据表明，LAM特异性抗体可以预测HIV感染者的结核病进展。 阴性个体，它们可以在体外赋予针对Mtb感染的保护，并且它们对 结核分枝杆菌在不同的临床菌株之间有差异。与TB进展的免疫相关性最相关的LAM表位， 感染的控制，其在结核分枝杆菌临床分离株中的流行率，以及LAM抗体的功能机制- 调解仍不明确。本文提出的研究旨在：1）确定预测结核病的体液特征 在HIV合并感染情况下的进展，2）确定LAM抗体应答的广度和特异性 抗全球Mtb分离株，和3）定义LAM抗体介导的效应子功能， 针对全球Mtb菌株的控制。这些目标将通过一个艾滋病毒合并感染者的国际队列来实现。 结核病进展者，并利用创新的方法，包括一个强大的系统免疫学平台， 一组合成寡糖，临床Mtb分离株的条形码文库，并在体外进行验证 抗菌功能测定。 候选人目前是哈佛医学院的医学讲师和助理 布里格姆妇女医院传染病科医生，正在进行一项研究 80%的时间。该建议得到了体液免疫学专家导师Galit Alter博士的支持 MGH、麻省理工学院和哈佛的Ragon研究所，以及分枝杆菌多样性方面的专家共同导师Sarah博士 财富在哈佛公共卫生学院。培训计划将候选人之前的研究生工作结合起来， 糖生物学，在体液免疫学，微生物学和生物信息学方面有专门的培训，以及正在进行的 专业发展和负责任地进行研究课程。完成这一全面 培训计划将确保候选人成功发展独特的独立翻译研究 该项目专注于对结核分枝杆菌聚糖的体液应答。